title: Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study.
abstract: Invasive aspergillosis (IA) is a serious hazard to high-risk haematological patients. There are increasing reports of azole-resistant Aspergillus spp. This study assessed the epidemiology of IA and azole-resistant Aspergillus spp. in patients with acute leukaemia in Germany. A prospective multicentre cohort study was performed in German haematology/oncology centres. The incidence of probable and proven aspergillosis according to the revised EORTC/MSG criteria was assessed for all patients with acute leukaemia [acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)]. Cases were documented into a web-based case report form, and centres provided data on standards regarding prophylactic and diagnostic measures. Clinical isolates were screened centrally for azole resistance and, if applicable, underlying resistance mechanisms were analysed. Between September 2011 and December 2013, 179 cases of IA [6 proven (3.4%) and 173 probable (96.6%)] were diagnosed in 3067 patients with acute leukaemia. The incidence of IA was 6.4% among 2440 AML patients and 3.8% among 627 ALL patients. Mortality at Day 84 was 33.8% (49/145) and attributable mortality was 26.9% (39/145). At Day 84, 53 patients (29.6%) showed a complete response, 25 (14.0%) a partial response and 17 (9.5%) a deterioration or failure. A total of 77 clinical Aspergillus fumigatus isolates were collected during the study period. Two episodes of azole-resistant IA (1.1%) were caused by a TR/L98H mutation in the cyp51A gene. With only two cases of IA due to azole-resistant A. fumigatus, a change of antifungal treatment practices in Germany does not appear warranted currently.
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Koehler
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany; German Centre for Infection Research, Partner Site Bonn-Cologne, Cologne, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hamprecht
authors.affiliation: Institut für Medizinische Mikrobiologie-Universitätsmedizin Göttingen, Göttingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bader
authors.affiliation: Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bekeredjian-Ding
authors.affiliation: Department of Haematology and Oncology, Mannheim University Hospital, University of Heidelberg, Mannheim, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Buchheidt
authors.affiliation: Friedrich Loeffler Institute for Medical Microbiology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Doelken
authors.affiliation: Institute of Hygiene and Microbiology, University of Würzburg, Würzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Elias
authors.affiliation: Department of Haematology, Oncology, Haemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Haase
authors.affiliation: Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Hahn-Ast
authors.affiliation: Medical Clinic IV, Haematology and Oncology, Neuperlach Hospital, Munich, Germany.
authors.forename: Meinolf
authors.initials: M
authors.lastname: Karthaus
authors.affiliation: Martin Luther University Halle-Wittenberg, Institute for Medical Microbiology, Halle (Saale), Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kekulé
authors.affiliation: University Hospital of Jena, Institute of Medical Microbiology, Jena, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Keller
authors.affiliation: Department of Haematology and Oncology, Klinikum Frankfurt Oder, Frankfurt, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kiehl
authors.affiliation: Medizinische Klinik 5, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Krause
authors.affiliation: Department of Haematology, Oncology, Haemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Krämer
authors.affiliation: Institut für Medizinische Mikrobiologie-Universitätsmedizin Göttingen, Göttingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Neumann
authors.affiliation: Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Rohde
authors.affiliation: University Hospital of Jena, Institute of Medical Microbiology, Jena, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: La Rosée
authors.affiliation: Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Ruhnke
authors.affiliation: Department of Internal Medicine II, Hubertus Wald Tumor Center-University Cancer Center Hamburg, Hamburg, Germany.
authors.forename: Philippe
authors.initials: P
authors.lastname: Schafhausen
authors.affiliation: Department of Haematology and Oncology, Medical Center, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Schalk
authors.affiliation: Friedrich Loeffler Institute for Medical Microbiology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schulz
authors.affiliation: Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwartz
authors.affiliation: Department A of Internal Medicine, University Hospital of Münster, Münster, Germany.
authors.forename: Gerda
authors.initials: G
authors.lastname: Silling
authors.affiliation: Klinik für Hämatologie und Onkologie, St Antonius Hospital Eschweiler, Eschweiler, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Staib
authors.affiliation: Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ullmann
authors.affiliation: Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Vergoulidou
authors.affiliation: Martin Luther University Halle-Wittenberg, Institute for Medical Microbiology, Halle (Saale), Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weber
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; German Centre for Infection Research, Partner Site Bonn-Cologne, Cologne, Germany; Clinical Trials Centre Cologne, ZKS Köln, Köln, Germany.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; German Centre for Infection Research, Partner Site Bonn-Cologne, Cologne, Germany. Electronic address: maria.vehreschild@uk-koeln.de.
authors.forename: Maria J G T
authors.initials: MJ
authors.lastname: Vehreschild
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects* / Q000302:isolation & purification; D001393:Azoles / Q000494:pharmacology*; D025141:Drug Resistance, Fungal; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D055744:Invasive Pulmonary Aspergillosis / Q000453:epidemiology* / Q000382:microbiology; D015470:Leukemia, Myeloid, Acute / Q000150:complications*; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications*; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D001393:Azoles
keywords: Acute lymphoblastic leukaemia; Acute myeloid leukaemia; Aspergillus fumigatus; Posaconazole; Voriconazole