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

L. Vanderbeke, N.A.F. Janssen, D.C.J.J. Bergmans, M. Bourgeois, J.B. Buil, Y. Debaveye, P. Depuydt, S. Feys, G. Hermans, O. Hoiting, B. van der Hoven, C. Jacobs, K. Lagrou, V. Lemiale, P. Lormans, J. Maertens, P. Meersseman, B. Megarbane, S. Nseir, J.A.H. van OersM. Reynders, B.J.A. Rijnders, J.A. Schouten, I. Spriet, K. Thevissen, A.W. Thille, R. Van Daele, F.L. van de Veerdonk, P.E. Verweij, A. Wilmer, R.J.M. Bruggemann, J. Wauters*, Dutch Belgian Mycosis Study Grp

*Corresponding author for this work

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Abstract

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.
Original languageEnglish
Pages (from-to)674-686
Number of pages13
JournalIntensive Care Medicine
Volume47
Issue number6
DOIs
Publication statusPublished - 1 Jun 2021

Keywords

  • Aspergillosis
  • Influenza
  • Posaconazole
  • Critical illness
  • Prophylaxis
  • AZOLE RESISTANCE
  • PROPHYLAXIS
  • SURVEILLANCE
  • FLUCONAZOLE
  • FUMIGATUS
  • VIRUS

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