• Lore Vanderbeke, Nico A F Janssen, BergmansDennis C J JDCJJ0000-0002-4224-6426Department of Intensive Care Medicine, Maastricht University Medical Center, Maastricht, The Netherlands., Marc Bourgeois, Jochem B Buil, Yves Debaveye, Pieter Depuydt, Simon Feys, Greet Hermans, Oscar Hoiting, Ben van der Hoven, Cato Jacobs, Katrien Lagrou, Virginie Lemiale, Piet Lormans, Johan Maertens, Philippe Meersseman, Bruno Mégarbane, Saad Nseir, Jos A H van Oers, Marijke Reynders, RijndersBart J ABJA0000-0003-3343-9610Department of Internal Medicine, Section of Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands., Jeroen A Schouten, Isabel Spriet, Karin Thevissen, Arnaud W Thille, Ruth Van Daele, Frank L van de Veerdonk, Paul E Verweij, Alexander Wilmer, BrüggemannRoger J MRJM0000-0002-7618-725XCenter of Expertise in Mycology Radboudumc/CWZ, Radboudumc Center for Infectious Diseases (RCI), Nijmegen, The Netherlands.Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands., Joost Wauters, and Dutch-Belgian Mycosis Study Group.
• Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
• Intensive Care Med. 2021 Jun 1; 47 (6): 674-686.

PurposeInfluenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA.MethodsWe compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population).ResultsEighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment.ConclusionThe higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.

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