Publications by authors named "Paul E Verweij"

279 Publications

Chronic HIV infection induces transcriptional and functional reprogramming of innate immune cells.

JCI Insight 2021 Feb 25. Epub 2021 Feb 25.

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.

Chronic inflammation and immune dysfunction play a key role in the development of non-AIDS related comorbidities. The aim of our study was to characterize the functional phenotype of immune cells in people living with HIV (PLHIV). We enrolled a cross-sectional cohort study of PLHIV on stable antiretroviral therapy and healthy controls. We assessed ex vivo cytokine production capacity and transcriptomics of monocytes and T-cells upon bacterial, fungal and viral stimulation. PLHIV exhibited an exacerbated pro-inflammatory profile in monocyte-derived cytokines, but not in lymphocyte-derived cytokines. Particularly, the production of the IL-1β to imiquimod, E. coli LPS and Mycobacterium tuberculosis was increased, and this production correlated with plasma concentrations of hsCRP and sCD14. This increase in monocyte responsiveness remained stable over time in subsequent blood sampling after >1year. Transcriptome analyses confirmed priming of the monocyte IL-1β pathway, consistent with a monocyte trained immunity phenotype. Increased plasma concentrations of β-glucan, a well-known inducer of trained immunity, were associated with increased innate cytokine responses. Monocytes of PLHIV exhibit a sustained pro-inflammatory immune phenotype with priming of the IL-1β pathway. Training of the innate immune system in PLHIV likely plays a role in long-term HIV complications and provides a promising therapeutic target for inflammation-related comorbidities.
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http://dx.doi.org/10.1172/jci.insight.145928DOI Listing
February 2021

Proven Aspergillus flavus pulmonary aspergillosis in a COVID-19 patient; A case report and review of the literature.

Mycoses 2021 Feb 11. Epub 2021 Feb 11.

Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Severe COVID-19 patients complicated with aspergillosis are increasingly reported. We present a histopathological proven case of fatal COVID-19 associated pulmonary aspergillosis (CAPA), due to Aspergillus flavus. This report and existing published literature indicate diagnostic challenges and poor outcomes of CAPA in ICU-patients.
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http://dx.doi.org/10.1111/myc.13255DOI Listing
February 2021

Aspergillus fumigatus tryptophan metabolic route differently affects host immunity.

Cell Rep 2021 Jan;34(4):108673

Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy.

Indoleamine 2,3-dioxygenases (IDOs) degrade l-tryptophan to kynurenines and drive the de novo synthesis of nicotinamide adenine dinucleotide. Unsurprisingly, various invertebrates, vertebrates, and even fungi produce IDO. In mammals, IDO1 also serves as a homeostatic regulator, modulating immune response to infection via local tryptophan deprivation, active catabolite production, and non-enzymatic cell signaling. Whether fungal Idos have pleiotropic functions that impact on host-fungal physiology is unclear. Here, we show that Aspergillus fumigatus possesses three ido genes that are expressed under conditions of hypoxia or tryptophan abundance. Loss of these genes results in increased fungal pathogenicity and inflammation in a mouse model of aspergillosis, driven by an alternative tryptophan degradation pathway to indole derivatives and the host aryl hydrocarbon receptor. Fungal tryptophan metabolic pathways thus cooperate with the host xenobiotic response to shape host-microbe interactions in local tissue microenvironments.
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http://dx.doi.org/10.1016/j.celrep.2020.108673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844877PMC
January 2021

Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.

Lancet Infect Dis 2020 Dec 14. Epub 2020 Dec 14.

Faculty of Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Department I of Internal Medicine, European Excellence Center for Medical Mycology (ECMM), University Hospital Cologne, Cologne, Germany; Clinical Trials Centre Cologne, ZKS Köln, Cologne, Germany; German Center for Infection Research, Partner Site Bonn-Cologne, Cologne, Germany. Electronic address:

Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.
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http://dx.doi.org/10.1016/S1473-3099(20)30847-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833078PMC
December 2020

Parasexual recombination enables to persist in cystic fibrosis.

ERJ Open Res 2020 Oct 7;6(4). Epub 2020 Dec 7.

Laboratory of Genetics, Wageningen University and Research, Wageningen, the Netherlands.

is a saprobic fungus that causes a range of pulmonary diseases, some of which are characterised by fungal persistence such as is observed in cystic fibrosis (CF) patients. Creation of genetic variation is critical for to adapt to the lung environment, but biofilm formation, especially in CF patients, may preclude mutational supply in due to its confinement to the hyphal morphotype. We tested our hypothesis that genetic variation is created through parasexual recombination in chronic biofilms by phenotypic and genetic analysis of isolates cultured from different origins. As diploids are the hallmark of parasex, we screened 799 isolates obtained from patients with CF, chronic pulmonary lung disease and acute invasive aspergillosis, and from the environment for spore size. Benomyl sensitivity, nuclear content measurements through fluorescence-activated cell sorting and scanning electron microscopy were used to confirm the diploid state of large size spores. Whole genome sequencing was used to characterise diploid-associated genetic variation. We identified 11 diploids in isolates recovered from six of 11 (55%) CF patients and from one of 24 (4%) chronic aspergillosis patients, but not in 368 isolates from patients with acute infection and the environment. Diploid formation was associated with accumulation of mutations and variable haploid offspring including a voriconazole-resistant isolate. Parasexual recombination allows to adapt and persist in CF patients, and plays a role in azole resistance development. Our findings are highly significant for understanding the genetics and biology of in the human lung.
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http://dx.doi.org/10.1183/23120541.00020-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720686PMC
October 2020

Fungal infections should be part of the core outcome set for COVID-19.

Lancet Infect Dis 2020 Dec 7. Epub 2020 Dec 7.

Mycology-Parasitology Department, Hôpital Saint-Louis, Molecular Mycology Unit, CNRS UMR2000, National Reference Centre for Invasive Mycoses and Antifungals, Institut Pasteur, Université de Paris, Paris, France.

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http://dx.doi.org/10.1016/S1473-3099(20)30591-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832680PMC
December 2020

A mould infection in disguise.

Clin Microbiol Infect 2020 Nov 27. Epub 2020 Nov 27.

Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, the Netherlands; Center of Expertise in Mycology Radboudumc/CWZ, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.cmi.2020.11.020DOI Listing
November 2020

Phylogenomic analysis of a 55.1 kb 19-gene dataset resolves a monophyletic Fusarium that includes the Fusarium solani Species Complex.

Authors:
David M Geiser Abdullah Al-Hatmi Takayuki Aoki Tsutomu Arie Virgilio Balmas Irene Barnes Gary C Bergstrom M K K Bhattacharyya Cheryl L Blomquist Robert Bowden Balázs Brankovics Daren W Brown Lester William Burgess Kathryn Bushley Mark Busman José F Cano-Lira Joseph D Carrillo Hao-Xun Chang Chi-Yu Chen Wanquan Chen Martin I Chilvers Sofia Noemi Chulze Jeffrey J Coleman Christina A Cuomo Z Wilhelm de Beer G Sybren de Hoog Johanna Del Castillo-Múnera Emerson Del Ponte Javier Diéguez-Uribeondo Antonio Di Pietro Vérnonique Edel-Hermann Wade H Elmer Lynn Epstein Akif Eskalen Maria Carmela Esposto Kathryne L Everts Sylvia P Fernández-Pavía Gilvan Ferreira da Silva Nora A Foroud Gerda Fourie Rasmus J N Frandsen Stanley Freeman Michael Freitag Omer Frenkel Kevin K Fuller Tatiana Gagkaeva Donald Max Gardiner Anthony E Glenn Scott Gold Tom Gordon Nancy F Gregory Marieka Gryzenhout Josep Guarro Beth Gugino Santiago Gutiérrez Kim Hammond-Kosack Linda J Harris Mónika Homa Cheng-Fang Hong László Hornok Jenn-Wen Huang Macit Ilkit Adriaana Jacobs Karin Jacobs Cong Jiang Maria Del Mar Jimenez-Gasco Seogchan Kang Matthew T Kasson Kemal Kazan John Carlyle Kennell HyeSeon Kim Harold Corby Kistler Gretchen A Kuldau Tomasz Kulik Oliver Kurzai Imane Laraba Matthew H Laurence Theresa Yun Lee Yin-Won Lee Yong-Hwan Lee John F Leslie Edward C Y Liew Lily W Lofton Antonio Logrieco Manuel Sánchez López-Berges Alicia Graciela Luque Erik Lysøe Li-Jun Ma Robert E Marra Frank N Martin Sara Ruth May Susan McCormick Chyanna T McGee Jacques F Meis Quirico Migheli Nik Mohd Izham Mohamed Nor Michel Monod Antonio Moretti Diane Mostert Giuseppina Mulé Françoise Munaut Gary P Munkvold Paul Nicholson Marcio Nucci Kerry O'Donnell Matias Pasquali Ludwig H Pfenning Anna Prigitano Robert Proctor Stéphane Ranque Stephen Rehner Martijn Rep Gerardo Rodríguez-Alvarado Lindy J Rose Mitchell George Roth Carmen Ruiz-Roldán Amgad A Saleh Baharuddin Salleh Hyunkyu Sang Mercedes Scandiani Jonathan Scauflaire David Schmale Dylan Pg Short Adnan Šišić Jason Smith Christopher W Smyth Hokyoung Son Ellie Spahr Jason E Stajich Emma Steenkamp Christian Steinberg Rajagopal Subramaniam Haruhisa Suga Brett Anthony Summerell Antonella Susca Cassandra Lynn Swett Christopher Toomajian Terry Jarianna Torres-Cruz Anna Maria Tortorano Martin Urban Lisa J Vaillancourt Gary E Vallad Theo van der Lee Dan Vanderpool Anne D van Diepeningen Martha Vaughan Eduard Venter Marcele Vermeulen Paul E Verweij Altus Viljoen Cees Waalwijk Emma C Wallace Grit Walther Jie Wang Todd Ward Brian Wickes Nathan P Wiederhold Michael J Wingfield Ana K M Wood Jin-Rong Xu X B Yang Tapani Yli-Matilla Sung-Hwan Yun Latiffah Zakaria Hao Zhang Ning Zhang Sean Zhang Xue Zhang

Phytopathology 2020 Nov 17. Epub 2020 Nov 17.

Northwest Agriculture and Forestry University, 12469, College of Plant Protection, Yangling, Shaanxi, China;

Scientific communication is facilitated by a data-driven, scientifically sound taxonomy that considers the end-user's needs and established successful practice. Previously (Geiser et al. 2013; Phytopathology 103:400-408. 2013), the Fusarium community voiced near unanimous support for a concept of Fusarium that represented a clade comprising all agriculturally and clinically important Fusarium species, including the F. solani Species Complex (FSSC). Subsequently, this concept was challenged by one research group (Lombard et al. 2015 Studies in Mycology 80: 189-245) who proposed dividing Fusarium into seven genera, including the FSSC as the genus Neocosmospora, with subsequent justification based on claims that the Geiser et al. (2013) concept of Fusarium is polyphyletic (Sandoval-Denis et al. 2018; Persoonia 41:109-129). Here we test this claim, and provide a phylogeny based on exonic nucleotide sequences of 19 orthologous protein-coding genes that strongly support the monophyly of Fusarium including the FSSC. We reassert the practical and scientific argument in support of a Fusarium that includes the FSSC and several other basal lineages, consistent with the longstanding use of this name among plant pathologists, medical mycologists, quarantine officials, regulatory agencies, students and researchers with a stake in its taxonomy. In recognition of this monophyly, 40 species recently described as Neocosmospora were recombined in Fusarium, and nine others were renamed Fusarium. Here the global Fusarium community voices strong support for the inclusion of the FSSC in Fusarium, as it remains the best scientific, nomenclatural and practical taxonomic option available.
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http://dx.doi.org/10.1094/PHYTO-08-20-0330-LEDOI Listing
November 2020

The Medical Triazole Voriconazole Can Select for Tandem Repeat Variations in Azole-Resistant Harboring TR/L98H Via Asexual Reproduction.

J Fungi (Basel) 2020 Nov 11;6(4). Epub 2020 Nov 11.

Laboratory for Genetics, Wageningen University and Research, 6708 PB Wageningen, The Netherlands.

Azole-resistant isolates recovered at high frequency from patients, harbor mutations that are associated with variation of promoter length in the gene. Following the discovery of the TR/L98H genotype, new variations in tandem repeat (TR) length and number of repeats were identified, as well as additional single nucleotide polymorphisms (SNPs) in the gene, indicating that the diversity of resistance mutations in is likely to continue to increase. Investigating the development routes of TR variants is critical to be able to design preventive interventions. In this study, we tested the potential effects of azole exposure on the selection of TR variations, while allowing haploid to undergo asexual reproduction. Through experimental evolution involving voriconazole (VOR) exposure, an isolate harboring TR/L98H evolved from a clinical TR/L98H ancestor isolate, confirmed by whole genome sequencing. TR/L98H was associated with increased expression and high VOR and posaconazole MICs, although additional acquired SNPs could also have contributed to the highly azole-resistant phenotype. Exposure to medical azoles was found to select for TR, thus supporting the possibility of in-host selection of TR variants.
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http://dx.doi.org/10.3390/jof6040277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711461PMC
November 2020

Coronavirus Disease 2019 (COVID-19) in a Patient with Disseminated Histoplasmosis and HIV-A Case Report from Argentina and Literature Review.

J Fungi (Basel) 2020 Nov 10;6(4). Epub 2020 Nov 10.

Unidad de Micología, Hospital de Infecciosas F. J. Muñiz B.A. Uspallata 2272, C1282 CABA, Argentina.

The disease caused by the new SARS-CoV-2, known as Coronavirus disease 2019 (COVID-19), was first identified in China in December 2019 and rapidly spread around the world. Coinfections with fungal pathogens in patients with COVID-19 add challenges to patient care. We conducted a literature review on fungal coinfections in patients with COVID-19. We describe a report of a patient with disseminated histoplasmosis who was likely infected with SARS-CoV-2 and experienced COVID-19 during hospital care in Buenos Aires, Argentina. This patient presented with advanced HIV disease, a well-known factor for disseminated histoplasmosis; on the other hand, we suspected that COVID-19 was acquired during hospitalization but there is not enough evidence to support this hypothesis. Clinical correlation and the use of specific and COVID-19 rapid diagnostics assays were key to the timely diagnosis of both infections, permitting appropriate treatment and patient care.
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http://dx.doi.org/10.3390/jof6040275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711963PMC
November 2020

A Multidisciplinary Approach to Fungal Infections: One-Year Experiences of a Center of Expertise in Mycology.

J Fungi (Basel) 2020 Nov 10;6(4). Epub 2020 Nov 10.

Center of Expertise in Mycology Radboudumc/CWZ, 6525 GA Nijmegen, The Netherlands.

Invasive fungal diseases (IFDs) often represent complicated infections in complex patient populations. The Center of Expertise in Mycology Radboudumc/CWZ (EMRC) organizes a biweekly multidisciplinary mycology meeting to discuss patients with severe fungal infections and to provide comprehensive advice regarding diagnosis and treatment. Here, we describe the patient population discussed at these meetings during a one-year period with regards to their past medical history, diagnosis, microbiological and other diagnostic test results and antifungal therapy. The majority of patients discussed were adults (83.1%), 62.5% of whom suffered from pulmonary infections or signs/symptoms, 10.9% from otorhinolaryngeal infections and/or oesophagitis, 9.4% from systemic infections and 9.4% from central nervous system infections. Among children, 53.8% had pulmonary infections or signs/symptoms, 23.1% systemic fungal infections and 23.1% other, miscellaneous fungal infections. 52.5% of adult patients with pulmonary infections/symptoms fulfilled diagnostic criteria for chronic pulmonary aspergillosis (CPA). Culture or polymerase chain reaction (PCR) demonstrated fungal pathogens in 81.8% of patients, most commonly . A multidisciplinary mycology meeting can be a useful addition to the care for patients with (I)FDs and can potentially aid in identifying healthcare and research needs regarding the field of fungal infections. The majority of patients discussed at the multidisciplinary meetings suffered from pulmonary infections, predominantly CPA.
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http://dx.doi.org/10.3390/jof6040274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712561PMC
November 2020

Dynamics of Aspergillus fumigatus in Azole Fungicide-Containing Plant Waste in the Netherlands (2016-2017).

Appl Environ Microbiol 2021 01 4;87(2). Epub 2021 Jan 4.

Laboratory of Genetics, Wageningen University, Wageningen, the Netherlands.

The treatment of patients suffering from diseases is hampered due to infections with that are already resistant to medical azoles. Previous work has suggested that likely gains resistance through environmental azole exposure in so-called hot spots. Here, we investigated resistance dynamics over time at three sites at which farmers used azole fungicides for crop protection. Over 16 months, 114 samples were taken from stockpiles of decaying plant waste. and azole fungicide residues were ubiquitously present in the plant waste. On average, 10 CFU/g was recovered, of which roughly half were itraconazole and tebuconazole resistant. Similar tandem repeat-mediated resistance mechanisms were found in colonies cultured from plant waste as reported in clinical azole-resistant isolates. Our results show a consistent high burden of azole-resistant in azole-containing plant waste and underscores the need to further investigate resistance-reducing interventions and transmission routes. is consistently present independently on season at a high abundance in plant waste material throughout the sampling period. Our study confirmed that long-term storage sites of azole-containing decaying plant material can indeed be considered hot spots, which can sustain resistance development and maintenance in Roughly half of individual isolates were azole resistant and carried genetic mutations that are highly similar to those found in patients with azole-resistant invasive aspergillosis. Our work suggests that environmental sources of azole resistance in may be important, underscoring the need for further studies on environment-to-patient transmission routes.
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http://dx.doi.org/10.1128/AEM.02295-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783342PMC
January 2021

Gene Mutation Prevalence in Triazole-Resistant Clinical Isolates.

J Fungi (Basel) 2020 Oct 16;6(4). Epub 2020 Oct 16.

Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Bacteriology and Mycology, KU Leuven, 3000 Leuven, Belgium.

Recently, mutations in the -encoding gene (), a gene involved in ergosterol production, were associated with triazole-resistance in . In this study, we determined the prevalence and characteristics of mutations in a collection of clinical triazole-resistant isolates collected during 2001-2019 from two international mycology reference centers: the Belgian National Reference Center for Mycosis and the Center of Expertise in Mycology Radboudumc/CWZ. Clinical isolates with and without gene mutations and randomly selected wild-type (WT) controls were included. Isolates were characterized by in vitro susceptibility testing, and sequencing, and short tandem repeat typing. Available clinical records were analyzed for previous triazole exposure. In 23 isolates (24%) of the 95 triazole-resistant isolates, gene mutations were observed; including 5/23 (22%) isolates without gene mutations and 18/72 (25%) with mutations. Four previously described gene mutations (E105K, G307R/D, G466V, and S541G) and two novel mutations (W273S and L304P) were found; 4/23 (17%) in the sterol-sensing-domain region. No triazole-antifungal exposure was reported in 75% (9/12) of patients harboring an isolate with gene mutations. Three of 39 WT isolates (8%) contained a gene mutation; E105K (2-isolates) and S541G. gene mutations were predominantly found in with mutations with voriconazole MICs ≥ 8 mg/L.
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http://dx.doi.org/10.3390/jof6040227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711918PMC
October 2020

Does Pulmonary Aspergillosis Complicate Coronavirus Disease 2019?

Crit Care Explor 2020 Sep 15;2(9):e0211. Epub 2020 Sep 15.

Medical Intensive Care Unit, UZLeuven, Leuven, Belgium.

Objectives: coinfection in coronavirus disease 2019 patients has rarely been described but may be occurring among coronavirus disease 2019 patients admitted to ICUs. Previous reports of viral coinfections with , including influenza-associated pulmonary aspergillosis, suggest that coronavirus disease 2019-associated aspergillosis is plausible. This report aims to summarize what is known about coronavirus disease 2019 complicated by , introduces coronavirus disease 2019-associated pulmonary aspergillosis as a possible clinical entity, and describes reasons clinical suspicion of is warranted in the critical care setting.

Data Sources: We summarize the available evidence suggesting the existence of coinfection among severe coronavirus disease 2019 patients. This includes published coronavirus disease 2019 patient case series, a case description, and a review of potential biologic mechanisms.

Study Selection: Reports of coronavirus disease 2019 patient attributes were selected if they included clinical, microbiologic, or radiologic signs of invasive fungal infection.

Data Extraction: Data included in summary tables were identified through a literature search for coronavirus disease 2019-associated pulmonary aspergillosis.

Data Synthesis: We present descriptive data extracted from coronavirus disease 2019-associated pulmonary aspergillosis case series current at the time of article submission.

Discussion: Pulmonary aspergillosis is known to occur among influenza patients requiring intensive care and is associated with increased mortality. If coinfections are occurring among coronavirus disease 2019 patients, early clinical suspicion and testing are needed to understand the epidemiology of these infections and prevent associated mortality. As the coronavirus disease 2019 pandemic unfolds, reports on the existence of this coinfection are needed, and opportunities to contribute cases of coinfection among coronavirus disease 2019 patients to an ongoing registry are described.
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http://dx.doi.org/10.1097/CCE.0000000000000211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498132PMC
September 2020

Update on Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Identification of Filamentous Fungi.

J Clin Microbiol 2020 Nov 18;58(12). Epub 2020 Nov 18.

Radboud University Medical Center, Department of Medical Microbiology, Nijmegen, the Netherlands.

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS)-based species identification has found its place in many clinical routine diagnostic laboratories over the past years, allowing significantly reduced turnaround times and high-precision results. With regard to MALDI-TOF MS for filamentous fungi, here, we discuss different approaches for sample processing and growth conditions before analysis. In particular, we review the performances of different commercially available databases as well as the potential of complementary (self-constructed) in-house databases.
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http://dx.doi.org/10.1128/JCM.01263-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685878PMC
November 2020

No to : Phylogenomic and Practical Reasons for Continued Inclusion of the Fusarium solani Species Complex in the Genus .

mSphere 2020 09 16;5(5). Epub 2020 Sep 16.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

This article is to alert medical mycologists and infectious disease specialists of recent name changes of medically important species of the filamentous mold species can cause localized and life-threating infections in humans. Of the 70 species that have been reported to cause infections, close to one-third are members of the species complex (FSSC), and they collectively account for approximately two-thirds of all reported infections. Many of these species were recently given scientific names for the first time by a research group in the Netherlands, but they were misplaced in the genus In this paper, we present genetic arguments that strongly support inclusion of the FSSC in There are potentially serious consequences associated with using the name for species because clinicians need to be aware that fusaria are broadly resistant to the spectrum of antifungals that are currently available.
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http://dx.doi.org/10.1128/mSphere.00810-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494836PMC
September 2020

Contact lens-related fungal keratitis.

Lancet Infect Dis 2020 09;20(9):1100

Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.

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http://dx.doi.org/10.1016/S1473-3099(20)30126-2DOI Listing
September 2020

Ventilator-associated pneumonia involving in a patient with coronavirus disease 2019 (COVID-19) from Argentina.

Med Mycol Case Rep 2021 Mar 5;31:19-23. Epub 2020 Jul 5.

Sección Micología, División Infectología, Hospital de Clínicas "José de San Martin", Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.

Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2, emerged in Wuhan, China, in December 2019 and rapidly spread around the world. Invasive aspergillosis has been reported as a complication of severe influenza pneumonia among intensive care patients. Similarities between COVID-19 and influenza pneumonia, together with limited published case series, suggest that aspergillosis may be an important complication of COVID-19. This report describes a case of ventilator-associated pneumonia involving in a patient with COVID-19 from Buenos Aires, Argentina.
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http://dx.doi.org/10.1016/j.mmcr.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335419PMC
March 2021

Diagnosing COVID-19-associated pulmonary aspergillosis.

Lancet Microbe 2020 Jun 10;1(2):e53-e55. Epub 2020 May 10.

Division of Infectious Diseases and Global Health, University of California San Diego, La Jolla, CA, USA.

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http://dx.doi.org/10.1016/S2666-5247(20)30027-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211496PMC
June 2020

Suboptimal Dosing of Fluconazole in Critically Ill Patients: Time To Rethink Dosing.

Antimicrob Agents Chemother 2020 09 21;64(10). Epub 2020 Sep 21.

Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Pharmacy, Nijmegen, The Netherlands

Fluconazole is frequently used for the treatment of invasive infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target AUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.).
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http://dx.doi.org/10.1128/AAC.00984-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508595PMC
September 2020

The challenge of managing COVID-19 associated pulmonary aspergillosis.

Clin Infect Dis 2020 Aug 18. Epub 2020 Aug 18.

Center of Expertise in Mycology Radboudumc/ CWZ and Radboud Center for Infectious Diseases, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1093/cid/ciaa1211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454346PMC
August 2020

Reply to Fekkar : Fungal Infection during COVID-19: Does Mean Secondary Invasive Aspergillosis?

Am J Respir Crit Care Med 2020 09;202(6):903-904

Radboud University Medical Centre Nijmegen, the Netherlands and.

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http://dx.doi.org/10.1164/rccm.202006-2241LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491394PMC
September 2020

Aspergillus fumigatus and pan-azole resistance: who should be concerned?

Curr Opin Infect Dis 2020 08;33(4):290-297

Department of Medical Microbiology, Radboud University Medical Center, and Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.

Purpose Of Review: Although clinical outcomes in the treatment of aspergillosis have markedly improved with the availability of newer triazoles, the development of resistance to these antifungals, especially in Aspergillus fumigatus, is a growing concern. The purpose of this review is to provide an update on azole resistance mechanisms and their epidemiology in A. fumigatus, the clinical implications of azole resistance, and to discuss future treatment options against azole-resistant aspergillosis.

Recent Findings: Resistance may develop through either patient or environmental azole exposure. Environmental exposure is the most prevalent means of resistance development, and these isolates can cause disease in various at-risk groups, which now include those with influenza, and potentially COVID-19. Although current treatment options are limited, newer therapies are in clinical development. These include agents with novel mechanisms of action which have in vitro and in vivo activity against azole-resistant A. fumigatus.

Summary: Azole-resistant A. fumigatus is an emerging threat that hampers our ability to successfully treat patients with aspergillosis. Certain geographic regions and patient populations appear to be at increased risk for this pathogen. As new patient groups are increasingly recognized to be at increased risk for invasive aspergillosis, studies to define the epidemiology and management of azole-resistant A. fumigatus are critically needed. While treatment options are currently limited, new agents under clinical development may offer hope.
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http://dx.doi.org/10.1097/QCO.0000000000000662DOI Listing
August 2020

Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion.

Intensive Care Med 2020 Aug 22;46(8):1524-1535. Epub 2020 Jun 22.

Centre of Expertise in Mycology Radboudumc/CWZ, Radboudumc Center for Infectious Diseases (RCI), Nijmegen, The Netherlands.

Purpose: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies.

Methods: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus.

Results: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung.

Conclusion: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA.
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http://dx.doi.org/10.1007/s00134-020-06091-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306567PMC
August 2020

Paradoxal Trends in Azole-Resistant Aspergillus fumigatus in a National Multicenter Surveillance Program, the Netherlands, 2013-2018.

Emerg Infect Dis 2020 07;26(7):1447-1455

We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR/L98H (69%) and TR/Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR/L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR/L98H isolates, which hampers the use of current PCR-based resistance tests.
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http://dx.doi.org/10.3201/eid2607.200088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323544PMC
July 2020

Evaluation of a New Culture Protocol for Enhancing Fungal Detection Rates in Respiratory Samples of Cystic Fibrosis Patients.

J Fungi (Basel) 2020 Jun 9;6(2). Epub 2020 Jun 9.

Department of Medical Microbiology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

Cystic fibrosis (CF) can be complicated by fungal infection of the respiratory tract. Fungal detection rates in CF sputa are highly dependent on the culture protocol and incubation conditions and thus may lead to an underestimation of the true prevalence of fungal colonization. We conducted a prospective study to evaluate the additional value of mucolytic pre-treatment, increased inoculum (100 µL), additional fungal culture media (Sabouraud agar; SAB, Medium B+, selective agar; SceSel+ and Dichloran-Glycerol agar; DG18) and longer incubation time (3 weeks) compared with our current protocol. Using the new protocol, we prospectively analyzed 216 expectorated sputum samples from adult and pediatric CF patients ( = 77) and compared the culture yield to a three year retrospective cohort that used direct 10 µL loop inoculation on SAB with 5 days incubation (867 sputum samples/103 patients). Detection rates for molds increased from 42% to 76% ( < 0.0001). Twenty-six percent of cultures were polymicrobial in the prospective cohort as opposed to 4.7% in the retrospective cohort ( < 0.0001). Colonization rate with increased from 36% to 57%. SAB and DG18 showed the highest detection rates for all molds (SAB 58.6%; DG18 56.9%) and DG18 had the best performance for molds other than . The larger sample volume and longer incubation also contributed to the increased recovery of molds. The introduction of a modified fungal culture protocol leads to a major increase in detection rate and the diversity of molds, which influences fungal epidemiology and may have implications for treatment decisions.
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http://dx.doi.org/10.3390/jof6020082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345163PMC
June 2020

Invasive Tracheobronchitis Emerging as a Highly Lethal Complication of Severe Influenza.

Am J Respir Crit Care Med 2020 09;202(5):646-648

Center of Expertise in Mycology Radboudumc/CWZ Nijmegen, the Netherlands.

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http://dx.doi.org/10.1164/rccm.202005-1883EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462390PMC
September 2020

Antifungal Activity of Antimicrobial Peptides and Proteins against .

J Fungi (Basel) 2020 May 18;6(2). Epub 2020 May 18.

Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.

Antimicrobial peptides and proteins (AMPs) provide an important line of defence against invading microorganisms. However, the activity of AMPs against the human fungal pathogen remains poorly understood. Therefore, the aim of this study was to characterise the anti- activity of specific human AMPs, and to determine whether can possess resistance to specific AMPs, as a result of in-host adaptation. AMPs were tested against a wide range of clinical isolates of various origins (including cystic fibrosis patients, as well as patients with chronic and acute aspergillosis). We also tested a series of isogenic isolates obtained from a single patient over a period of 2 years. A range of environmental isolates, obtained from soil in Scotland, was also included. Firstly, the activity of specific peptides was assessed against hyphae using a measure of fungal metabolic activity. Secondly, the activity of specific peptides was assessed against germinating conidia, using imaging flow cytometry as a measure of hyphal growth. We showed that lysozyme and histones inhibited hyphal metabolic activity in all the isolates tested in a dose-dependent fashion. In addition, imaging flow cytometry revealed that histones, β-defensin-1 and lactoferrin inhibited the germination of conidia.
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http://dx.doi.org/10.3390/jof6020065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345740PMC
May 2020

COVID-19-associated Pulmonary Aspergillosis.

Am J Respir Crit Care Med 2020 07;202(1):132-135

Amphia HospitalBreda, the Netherlands.

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http://dx.doi.org/10.1164/rccm.202004-1038LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328331PMC
July 2020