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

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.

Keywords: Aspergillosis; Critical illness; Influenza; Posaconazole; Prophylaxis.

Conflict of interest statement

JBB reports grants from F2G, grants from Gilead Sciences, grants from Thermo Fisher Scientific, outside the submitted work. KL received consultancy fees from MSD, SMB Laboratoires Brussels and Gilead, non-financial support from Pfizer and MSD, received speaker fees from Gilead Sciences, FUJIFILM WAKO and Pfizer and a grant from Thermo Fisher Scientific. VL reports financial support of Pfizer, Fisher Paykel, Gilead Sciences, Alexion and Celgene to her research group, outside the submitted work. JM reports grants, personal fees and non-financial support from Gilead Sciences, MSD and Pfizer; personal fees and non-financial support from Cidara, F2G and Mundipharma; outside the submitted work. AWT reports personal fees and non-financial support from Fisher&Paykel, outside the submitted work. RVD reports non-financial support from Pfizer and Gilead Sciences, outside the submitted work. LV reports non-financial support from Gilead Sciences, outside the submitted work. PEV reports grants from Mundipharma, grants from F2G, grants from Pfizer, grants from Thermofisher, grants from Gilead Sciences, non-financial support from IMMY, grants from Cidara, outside the submitted work. RJMB reports consultancy fees from Mundipharma, Cidara, Amplyx, F2G, Gilead, Pfizer and MSD, speaker fees from Pfizer and Gilead, grants from Pfizer, Gilead and MSD. JW received speakers fee from MSD, Pfizer and Gilead, consultancy fee from Gilead and he obtained investigator-initiated grants from Gilead, Pfizer and MSD.

Figures

Fig. 1

Trial profile. ICU intensive care unit, IAPA influenza-associated pulmonary aspergillosis, IPA invasive pulmonary aspergillosis, QTc corrected QT-interval

Fig. 2

Time to influenza-associated pulmonary aspergillosis. Data derived from modified intention-to-treat population; at 90 days after intensive care admission all patient data were censored. IAPA diagnosis based on modified AspICU criteria. CI confidence interval, HR hazard ratio, IAPA influenza-associated pulmonary aspergillosis, ICU intensive care unit, N° number, POS posaconazole prophylaxis, SOC standard-of-care