Pulmonary Aspergillosis in Critically Ill Coronavirus Disease 2019 Patients– A Multinational Observational Study by the European Confederation of Medical Mycology

Background: Coronavirus disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA) has emerged as a complication in critically ill COVID-19 patients. To determine the prevalence of CAPA in patients with COVID-19 in intensive care units (ICU) and to investigate risk factors for CAPA as well as outcome.  Methods: The European Confederation of Medical Mycology (ECMM) conducted a multinational study including 20 centers from nine different countries to assess epidemiology, risk factors, treatment and outcome of CAPA. CAPA was defined according to ECMM/ISHAM consensus definitions.  Findings: A total of 592 patients were included in this study, including 11 (1.9%) patients with histologically proven CAPA, 80 (13.5%) patients with probable CAPA, 18 (3%) with possible CAPA and 483 (81.6%) without CAPA. CAPA was diagnosed a median of 8 days (range 0-31) after ICU admission predominantly in older patients [adjusted hazard ratio (aHR) 1.04 per year] with any form of invasive respiratory support (HR 3.4) and receiving tocilizumab (HR 2.45). Median prevalence of CAPA per center was 10.7% (range 1.7% - 26.8%). CAPA was associated with significantly lower 90-day ICU survival rate (29% in patients with CAPA versus 57% in patients without CAPA; Mantel-Byar p<0.001) and remained an independent negative prognostic variable after adjusting for other predictors of survival.  Interpretation: Prevalence of CAPA varied between centers. CAPA was more prevalent among older patients receiving invasive ventilation and tocilizumab, and an independent strong predictor of ICU mortality. Funding: RR was supported by the NIHR Manchester Biomedical Research Centre. PK is supported by the German Federal Ministry of Research and Education and the State of North Rhine- Westphalia, Germany and has received non-financial scientific grants from the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. MH is supported by NIH and investigator initiated grants from Astellas, Gilead and Pfizer. Declaration of Interest: JP has received personal fees from Gilead Sciences and Pfizer, research funding from MSD outside of the submitted work and is stoke holder of AbbVie Inc and Novo Nordisk. JW reports grants and personal fees from Gilead and Pfizer: investigator-initiated grants, personal fees and also on-financial support from MSD, outside the submitted work. DRG reports an unconditional grant from Correvio Italia and a grant for his institution by Pfizer Inc. Outside the submitted work. JM reports grants, personal fees and non-financial support from MSD, grants, personal fees and nonfinancial support from Pfizer Inc., grants, personal fees and non-financial support from Gilead Sciences, personal fees and non-financial support from Astellas Pharam, personal fees and non-financial support from Cidara, personal fees and non-financial support from F2G, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from Takeda/Shire, outside of the submitted work. OAC reports grants and personal fees from Actelion, personal fees from Allecra Therapeutics, personal fees from Al-Jazeera Pharmaceuticals, grants and personal fees from Amplyx, grants and personal fees from Astellas, grants and personal fees from Basilea, personal fees from Biosys, grants and personal fees from Cidara, grants and personal fees from DaVolterra, personal fees from Entasis, grants and personal fees from F2G, grants and personal fees from Gilead, personal fees from Grupo Biotoscana, personal fees from IQVIA, grants from Janssen, personal fees from Matinas, grants from Medicines Company, grants and personal fees from MedPace, grants from Melinta Therapeutics, personal fees from Menarini, grants and personal fees from Merck/MSD, personal fees from Mylan, personal fees from Nabriva, personal fees from Noxxon, personal fees from Octapharma, personal fees from Paratek, grants and personal fees from Pfizer, personal fees from PSI, personal fees from Roche Diagnostics, grants and personal fees from Scynexis, personal fees from Shionogi, grants from DFG, German Research Foundation, grants from German Federal Ministry of Research and Education, grants from Immunic, personal fees from Biocon, personal fees from CoRe Consulting, personal fees from Molecular Partners, from MSG-ERC, from Seres, other from Wiley (Blackwell), outside the submitted work. LD has received personal fees from Gilead Sciences outside of the submitted work. JS has received lecture honoraria from Gilead and Pfizer, outside of the submitted work. MB has received funding for scientific advisory boards, travel and speaker honoraria from Angelini, Astellas, Bayer, BioMerieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer and Shionogi. RRR has received speaker honoraria from Astellas Pharma, Gilead Sciences, Pfizer and research funding from Associates of Cape Cod. PK is supported by the German Federal Ministry of Research and Education and the State of North Rhine- Westphalia, Germany and has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging- Associated Diseases, University of Cologne, Cologne, Germany, and received lecture honoraria from and/or is advisor to Akademie fur Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, MSD Sharp & Dohme GmbH, Noxxon N.V., and University Hospital, LMU Munich outside the submitted work. KL received consultancy fees from SMB Laboratoires Brussels, MSD and Gilead, travel support from Pfizer, speaker fees from FUJIFILM WAKO, Pfizer and Gilead and a service fee from Thermo fisher Scientific. MH received research funding from Gilead Sciences, Astellas, Scynexis, F2G and Pfizer, all outside the submitted work. All other authors declare no conflict of interest for this study. Ethical Approval: The study protocol and all study-related procedures were approved by the Medical University of Graz (EC #32-296 ex 19/20) and the other participating centers which all followed the local ethical requirements. The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. FungiScope® was approved by the local Institutional Review Board and Ethics Committee of the University Hospital Cologne, Germany (Study ID: 05-102).