Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial

• Published in: Intensive care medicine Vol. 47; no. 6; pp. 674 - 686
• Main Authors: Vanderbeke, Lore, Janssen, Nico A. F., Bergmans, Dennis C. J. J., Bourgeois, Marc, Buil, Jochem B., Debaveye, Yves, Depuydt, Pieter, Feys, Simon, Hermans, Greet, Hoiting, Oscar, van der Hoven, Ben, Jacobs, Cato, Lagrou, Katrien, Lemiale, Virginie, Lormans, Piet, Maertens, Johan, Meersseman, Philippe, Mégarbane, Bruno, Nseir, Saad, van Oers, Jos A. H., Reynders, Marijke, Rijnders, Bart J. A., Schouten, Jeroen A., Spriet, Isabel, Thevissen, Karin, Thille, Arnaud W., Van Daele, Ruth, van de Veerdonk, Frank L., Verweij, Paul E., Wilmer, Alexander, Brüggemann, Roger J. M., Wauters, Joost
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2021; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Adult; Anesthesiology; Antifungal agents; Aspergillosis; Biological products industry; Cardiology and cardiovascular system; Comparative analysis; Critical Care Medicine; Critical Illness; Disease prevention; Emergency Medicine; Emerging diseases; Fungal infections; Fungicides; Health aspects; Human health and pathology; Humans; Infectious diseases; Influenza; Influenza, Human - complications; Influenza, Human - drug therapy; Influenza, Human - prevention & control; Intensive; Intensive care; Intensive Care Units; Intravenous administration; Invasive Pulmonary Aspergillosis - drug therapy; Invasive Pulmonary Aspergillosis - prevention & control; Life Sciences; Medicine; Medicine & Public Health; Mortality; NCT; NCT03378479; Original; Pain Medicine; Pediatrics; Pharmaceutical industry; Pneumology/Respiratory System; Posaconazole; Prevention; Prophylaxis; Pulmonary aspergillosis; Pulmonology and respiratory tract; Respiratory failure; Strategic planning (Business); Toxicology; Triazoles; United States; Critical illness; Posaconazole; Influenza; Aspergillosis; Prophylaxis
• ISSN: 0342-4642; 1432-1238
• DOI: 10.1007/s00134-021-06431-0

Purpose Influenza-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. Methods We 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). Results Eighty-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. Conclusion The 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.